Cytokines released by human tumors are independent from cancer histotype

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BACKGROUND In the tumor microenvironment, immune, stromal and cancer cells interact. They communicate in paracrine and autocrine manners via secreted cytokines, altering anti-tumor immunity. The pattern consisting of the relative secretions of these proteins is referred-to as the "immune secretome". To date, the immune secretome of human cancers remains largely unexplored. Herein, we describe the dominant cytokines released by human tumors. METHODS We analyzed multiple prospectively collected samples of tumoral and peritumoral tissues. After surgical resection, we promptly titered 40 cytokines released by the samples. RESULTS Macrophage migration Inhibitory Factor (MIF), Chemokine (C-C motif) ligand 21 (CCL21) and Interleukin 16 (IL-16) were the most strongly detected cytokines in the human tumor secretome. Surprisingly, GM-CSF, IL-10 and IL-2 were undetectable or measured at low levels. Moreover, we observed significant differences in cytokine secretions across different tumor histotypes: while liver metastases, head and neck carcinomas and thyroid tumors secreted large amounts of cytokines (10 3 to 10 5 pg/ gram of tissue across most analytes), the other histotypes secreted at least 10 to 100 times less of each cytokine per gram of tissue. The liver metastases secreted particularly high amounts of CCL21, IL-16, CXCL10, CCL24 and CCL15, but had low CD45+ cell infiltrates compared to primary tumors. We also found that tumor tissues secreted significantly higher quantities of CXCL1 and CXCL9 than surrounding healthy tissues. CONCLUSIONS Tumor histology is not associated with a specific secretome, but subgroups of patients share similar secretome profiles independently from their cancer type. This finding supports the development of biology-oriented tumor-agnostic immunotherapy strategies. As the secretome interacts with tumor-infiltrating T-cells, the cytokines identified within it become potential therapeutic targets for personalized cancer immunotherapy.

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